Synthetic glucocorticoids remain among the most effective agents for the treatment of chronic inflammatory diseases. However, major side effects severely limit their therapeutic use. Physiologic and therapeutic activities of glucocorticoids are mediated by a nuclear receptor belonging to a superfamily of ligand-inducible transcription factors that, in addition to directly regulating their cognate gene programs, can also interfere with other signalling pathways, such as those utilizing NF-κB.
NF-κB is an inducible transcription factor complex which regulates the expression of various genes involved in inflammatory and immune responses. It is activated upon exposure of cells to pro-inflammatory cytokines (TNF, IL-1), oxidants (hydrogen peroxide, ozone, superoxide anions), bacterial compounds (LPS), viral products (dsRNA, HTLV-I Tax protein), PKC activators (phorbol esters, platelet activating factor) and UV- or γ-irradiation.
NF-κB is a promising target for anti-inflammatory and immunosuppressive therapies. Inhibition of NF-κB activity by glucocorticoids (GC) has been well documented, although gene stimulatory effects by GC have also been observed.
Although GC remain, as mentioned above, among the most potent immunosuppressive and anti-inflammatory drugs currently available, and are especially effective in the treatment of chronic asthma or rheumatoid arthritis, side effects such as hypothalamic-pituitary-adrenal axis insufficiency, diabetes, altered lipid metabolism, steroid myopathy, osteoporosis, and infectious and neuropsychiatric complications limit the therapeutic use of classical glucocorticoid agonists. Therefore there is a need to investigate and search for novel compounds that have anti-inflammatory properties without having severe side-effects.
Compound A (CpdA) or 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride is a stable analogue of the hydroxyphenylaziridine precursor found in the Namibian shrub Salsola tuberculatiformis Botschantzev (Louw, 1997). Contraceptive properties have been attributed to plants of the Salsola genus as early as 1902 and recognized and passed on through oral Bushman tradition (Brondegaard, 1973). Feeding experiments with the shrub indeed caused contraceptive effects in rats and prolonged gestation in sheep (van der Merwe, 1976; Basson, 1969). A study by van der Merwe et al. (1976) led also to the isolation of an active but very labile HPLC fraction from the dried plant material, a hydroxyphenylaziridine, and synthesis of a more stable but biologically active analogue, CpdA (Louw, 1997). Recent work performed by the group of Louw and co-workers set out to unravel the contraceptive mechanism of action and the molecular targets of this desert plant derivative analogue. Multiple levels of interference with endogenous glucocorticoid action were observed. From their results, it was concluded that CpdA disrupts the oestrus cycle of rats by interacting with glucocorticoid-binding proteins such as steroidogenic enzymes and plasma steroid-binding globulins, thereby altering the interaction between the hypothalamus, pituitary, adrenal gland and gonads (HPA axis versus HPG axis) (Louw, 1997 and 1999).